The high-affinity Trk and low-affinity p75NTR receptors play critical roles in the growth, differentiation, and survival or neurons and glial cells. Numerous reports support a cross talk between these neurotrophin signaling pathways that is likely critical in regulation of growth, differentiation, and survival. Furthermore, this interplay of signaling pathways likely requires a high degree of organization for optimal regulation. Therefore, the long-term objectives of this research are to define the molecular mechanisms that regulate cross talk between Trk A and p75NTR neurotrophin receptors and the functional significance of this cross talk in neuronal populations. Data presented herein strongly suggest that the Trk A and p75NTR pathways converge at the interaction of PI 3-kinase and acid sphingomyelinase (SMase). However, it remains unknown how PI 3-kinase interacts with acid SMase, Thus, the Specific Aims of this proposal are: 1) to determine the minimal binding domain within p85 that interacts with acid SMase an 2) to assess the role of the YXXM, NPXY, and proline-rich sequences of acid SMase in the interaction with p85.